KDM1A inhibitors for the treatment of disease
AssigneeImago Biosciences, Inc.
InventorsHugh Y. Rienhoff, Jr., John M. McCall, Michael Clare, Cassandra Celatka, Amy E. Tapper
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Abstract
Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation of cancer cells in a human or animal subject are also provided for the treatment of diseases such as acute myelogenous leukemia.
Claims10
A compound of Formula IV:
- or a salt, polymorph, or solvate thereof, wherein:
- Y is chosen from a bond, NR4a, O, C(O)NH, NHC(O), S, SO2, CHOH, and CH2;
- Z is chosen from a bond, NR4b, O, C(O)NH, NHC(O), S, SO2, and CH2;
- m is chosen from 0, 1, 2, 3, 4, and 5;
- n is chosen from 0, 1, 2, and 3;
- R1 and R2 are each independently chosen from alkyl, aminoalkyl, alkylsulfonylalkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, phenyl, biphenyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl and
- R1 and R2, together with the nitrogen to which they attach, form a nitrogen-containing heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R6 groups
- R4a and R4b are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl;
- R5 is chosen from aryl and heteroaryl, any of which may be optionally substituted with between 0 and 3 R6 groups;
- R6a is chosen from heteroaryl, cyano, and S(O)2N(CH3)2;
- each R6 is independently chosen from
- alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, deuterium, trideuteromethyl, amino, —COOH, —CONH2, —SO2CH3, cyano, spiro-heterocycloalkyl, heteroaryl, and oxo;
- and
- R7 and R8 are independently chosen from hydrogen, aryl, and lower alkyl;
- or R7 and R8 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with lower alkyl.
A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound, or a salt, polymorph, or solvate thereof, as disclosed herein, or a salt thereof, to a patient, wherein the effect is chosen from an elevation of red blood cell count, an elevation of the red blood cell count of red cells containing fetal hemoglobin, an elevation in the total concentration of fetal hemoglobin in red cells, an elevation in the total concentration of fetal hemoglobin in reticulocytes, an increase in the transcription of the gamma globin gene in bone marrow-derived red cell precursors, a reduction in the number of sickle cell crises a patient experiences over a unit period of time, a halt to or prevention of tissue damage caused by sickling cells, a reduction in the proportion of red cells that undergo sickling under physiological conditions of relative hypoxia as measured using patient blood in an in vitro assay, an increase in the amount of histone 3 lysine methylation at lysine position 4 (H3K4me1 and H3K4me2), and/or a decrease in the amount of histone 3 methylation at lysine position 9 (H3K9me1 or H3K4me2) near or at the gamma globin promoter as assayed by ChIP using cells derived from a treated patient.
Dependencies are inferred from the claim text.